Alvocidib, Cytarabine, and Mitoxantrone in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00795002
• Collaborator: (none)
• Enrollment: 78
• Locations: 2
• Arms: 2
• Duration (Months): 46
• Patients Per Site: 39
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This randomized phase II trial is studying two different schedules of alvocidib to compare how well they work when given together with cytarabine and mitoxantrone in treating patients with newly diagnosed acute myeloid leukemia. Drugs used in chemotherapy, such as alvocidib, cytarabine, and mitoxantrone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known which schedule of alvocidib is more effective when given together with cytarabine and mitoxantrone in treating patients with acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia	Drug: alvocidib; Drug: mitoxantrone hydrochloride; Drug: cytarabine; Other: pharmacological study; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To compare the efficacy of two different schedules (bolus vs "hybrid bolus-infusion") of alvocidib followed by cytarabine and mitoxantrone hydrochloride in patients with newly diagnosed acute myeloid leukemia (AML) with poor-risk features.

SECONDARY OBJECTIVES:

1. To compare the toxicities of these regimens. II. To determine the disease-free survival and overall survival of patients who demonstrate a response to these regimens.

2. To compare the pharmacokinetics of alvocidib when administered in two different schedules (bolus vs "hybrid bolus-infusion").

3. To describe alvocidib-induced alterations in AML blast cell expression of selected target mRNA and proteins.

4. To describe alvocidib-induced alterations in AML blast cell growth kinetic parameters.

OUTLINE: This is a multicenter study. Patients are stratified according to antecedent hematologic disorder of >= 6 months duration prior to transformation to acute myeloid leukemia (AML) and any prior antecedent therapy for myelodysplastic syndromes or myeloproliferative disorder. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.

ARM II: Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.

Patients achieving partial or complete response (CR) after the first course of treatment may receive a second course of treatment 35-63 days following blood count recovery and/or undergo allogeneic bone marrow transplantation. Patients >= 50 years of age with t (8;21), inv (16), or t(16;16) AML who achieve CR after the first course of treatment may receive 3-4 courses of high-dose cytarabine consolidation therapy.

Bone marrow and/or blood samples are collected at baseline and periodically during study for correlative laboratory studies, including pharmacokinetic studies by liquid chromatography and tandem mass spectrometry, analysis of blast cell growth kinetic parameters by flow cytometry, and blast cell expression of selected target mRNA and protein by quantitative RT-PCR and western blotting.

After completion of study therapy, patients are followed periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study Comparing Two Administration Schedules of Flavopiridol (Alvocidib, NSC 649890, IND 46, 211) Given in Timed Sequential Combination With Cytosine Arabinoside (Ara-C) and Mitoxantrone Hydrochloride for Adults With Newly Diagnosed, Previously Untreated, Poor Risk Acute Myelogenous Leukemias (AML)
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.	Drug: alvocidib; Given IV; Other Names: FLAVO flavopiridol HMR 1275 L-868275 ; Drug: mitoxantrone hydrochloride; Given IV; Other Names: CL 232315 DHAD DHAQ Novantrone ; Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Correlative studies
Experimental: Arm II Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.	Drug: alvocidib; Given IV; Other Names: FLAVO flavopiridol HMR 1275 L-868275 ; Drug: mitoxantrone hydrochloride; Given IV; Other Names: CL 232315 DHAD DHAQ Novantrone ; Drug: cytarabine; Given IV; Other Names: ARA-C arabinofuranosylcytosine arabinosylcytosine Cytosar-U cytosine arabinoside ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Complete Response [1 year]

   Bone marrow showing less than 5% leukemic blasts with normal maturation of all cell lines, an ANC of at least 1000/uL and a platelet count of 100,000/uL, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. Repeat marrow confirmation 4-6 weeks following the marrow documenting CR is not required due to the need for continued treatment in CR.

Secondary Outcome Measures

1. Number of Participants Experiencing Death From Any Cause Within 60 Days of Starting FLAM [60 days]

   Toxicity defined as death from any cause within 60 days of starting FLAM.

2. Disease-free Survival [up to 2 years]

   This will be defined as the time between study entry and the first date that recurrent or progressive disease is objectively documented, or death from any cause occurs.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Pathologically confirmed newly diagnosed acute myeloid leukemia (AML) meeting the following criteria:

• Subtypes M0, M1, M2, M4-7

• No acute promyelocytic leukemia (M3)

• At least 50 years of age OR >= 18 years of age with >= 1 of the following poor-risk disease features:

• Antecedent hematologic disorder, including myelodysplastic syndromes (MDS)-related AML or prior myeloproliferative disorder (MPD)

• Treatment-related AML, AML with trilineage dysplasia

• Myeloid sarcoma, myeloid proliferations related to Down Syndrome, or blastic plasmacytoid dendritic cell neoplasm

• AML with trilineage dysplasia

• AML with adverse cytogenetics (defined as -5/-5q; -7/-7q; abnormal 3q, 9q, 11q, 20q, 21q, or 17p; t[6;9]; t[9;22]; trisomy 8; trisomy 13, complex karyotypes [>= 3 unrelated abnormalities]),

• No hyperleukocytosis with >= 50,000 blasts/uL (leukapheresis or hydroxyurea allowed for cytoreduction immediately prior to the first dose of alvocidib)

• No active CNS leukemia

• ECOG performance status 0-2

• Serum creatinine =< 2.0 mg/dL

• ALT/AST =< 5 times upper limit of normal

• Bilirubin =< 2.0 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• No active uncontrolled infection

• Infection that is under active treatment allowed provided it is controlled with antibiotics

• No other life-threatening illness

• No mental deficits and/or psychiatric history that would preclude giving informed consent or following study requirements

• At least 24 hours since prior leukapheresis or hydroxyurea for cytoreduction

• Prior non-cytotoxic therapies (e.g., thalidomide or lenalidomide, interferon, cytokines, low-dose 5-azacytidine, or low-dose cytoxan) for MDS or MPD allowed

• Prior chemotherapy or bone marrow/stem cell transplantation for non-AML malignancy allowed

• No prior alvocidib

• No other concurrent chemotherapy, radiotherapy, or immunotherapy

• No other concurrent investigational or commercially-available antitumor therapies for AML

• LVEF >= 45%

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
2	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Judith Karp, Johns Hopkins University/Sidney Kimmel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00795002
• Other Study ID Numbers: NCI-2009-00298; NCI-2009-00298; CDR0000625222; J0856; 8237; P30CA006973; U01CA070095
• First Posted: Nov 21, 2008
• Last Update Posted: Aug 7, 2018
• Last Verified: Aug 1, 2018

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia, Monocytic, Acute; Leukemia, Myelomonocytic, Acute; Leukemia, Megakaryoblastic, Acute; Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes; Cytarabine; Mitoxantrone; Alvocidib

Study Results

Participant Flow

Recruitment Details	All newly diagnosed adults diagnosed with AML were considered for participation.Enrolled on study between November 20, 2008 and July 20, 2010.
Pre-assignment Detail	2 patients on each arm consented to study, but were screen failures and did not start treatment.

Arm/Group Title	Arm I	Arm II
Arm/Group Description	Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.	Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.
Period Title: Overall Study
STARTED	37	37
COMPLETED	37	37
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm I	Arm II	Total
Arm/Group Description	Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.	Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.	Total of all reporting groups
Overall Participants	39	39	78
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	27 69.2%	30 76.9%	57 73.1%
>=65 years	12 30.8%	9 23.1%	21 26.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (54)	59 (53)	60 (58)
Sex: Female, Male (Count of Participants)
Female	13 33.3%	20 51.3%	33 42.3%
Male	26 66.7%	19 48.7%	45 57.7%
Region of Enrollment (participants) [Number]
United States	39 100%	39 100%	78 100%

Outcome Measures

1. Primary Outcome

Title	Complete Response
Description	Bone marrow showing less than 5% leukemic blasts with normal maturation of all cell lines, an ANC of at least 1000/uL and a platelet count of 100,000/uL, absence of blast in peripheral blood, absence of identifiable leukemic cells in the bone marrow, clearance of disease-associated cytogenetic abnormalities, and clearance of any previously existing extramedullary disease. Repeat marrow confirmation 4-6 weeks following the marrow documenting CR is not required due to the need for continued treatment in CR.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

39 patients had been enrolled in each arm with two patients in each arm receiving incomplete therapy

Arm/Group Title	Arm I	Arm II
Arm/Group Description	Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.	Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.
Measure Participants	37	37
Number [participants]	24 61.5%	29 74.4%

2. Secondary Outcome

Title	Number of Participants Experiencing Death From Any Cause Within 60 Days of Starting FLAM
Description	Toxicity defined as death from any cause within 60 days of starting FLAM.
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

39 patients had been enrolled in each arm with two patients in each arm receiving incomplete therapy. Toxicity defined as death from any cause within 60 days of starting FLAM.

Arm/Group Title	Arm I	Arm II
Arm/Group Description	Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.	Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.
Measure Participants	37	37
Count of Participants [Participants]	3 7.7%	3 7.7%

3. Secondary Outcome

Title	Disease-free Survival
Description	This will be defined as the time between study entry and the first date that recurrent or progressive disease is objectively documented, or death from any cause occurs.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

39 patients had been enrolled in each arm with two patients in each arm receiving incomplete therapy.

Arm/Group Title	Arm I	Arm II
Arm/Group Description	Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.	Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.
Measure Participants	37	37
Median (95% Confidence Interval) [months]	13.6	12.0

Adverse Events

Time Frame	1 cycle of therapy
Arm/Group Title	Arm I		Arm II
Arm/Group Description	Patients receive alvocidib IV over 1 hour on days 1-3, cytarabine IV continuously over 72 hours on days 6-8, and mitoxantrone hydrochloride IV over 60-120 minutes on day 9.		Patients receive alvocidib IV over 30 minutes followed by alvocidib IV over 4 hours on days 1-3. Patients also receive cytarabine and mitoxantrone hydrochloride as in arm I.
All Cause Mortality
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/39 (20.5%)		8/39 (20.5%)
Cardiac disorders
Cardiac dysfunction	2/39 (5.1%)	2	2/39 (5.1%)	2
Gastrointestinal disorders
Oral and/or Gastrointestinal mucositis	2/39 (5.1%)	2	2/39 (5.1%)	2
Metabolism and nutrition disorders
Tumor Lysis Syndrome	4/39 (10.3%)	4	4/39 (10.3%)	4
Other (Not Including Serious) Adverse Events
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/39 (2.6%)		1/39 (2.6%)
General disorders
General disorders-other	1/39 (2.6%)	1	1/39 (2.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.